key: cord-0742177-hloi3vf8
authors: Huang, Jiana; Gao, Jiebing; Zhu, Wenliang; Feng, Ruiling; Liu, Qianru; Chen, Xiumin; Huang, Jingmin; Yang, Zhe; Lin, Xiufang; Zhang, Zuoquan; Lin, Yubi
title: Indicators and prediction models for the severity of Covid‐19
date: 2021-07-06
journal: Int J Clin Pract
DOI: 10.1111/ijcp.14571
sha: 8194d3a0452d7a2e29551e3ca1b8ef88544d5838
doc_id: 742177
cord_uid: hloi3vf8

OBJECTIVES: Coronavirus disease 2019 (Covid‐19) is outbreaking globally. We aimed to analyse the clinical characteristics, cardiac injury, electrocardiogram and computed tomography (CT) features of patients confirmed Covid‐19 and explored the prediction models for the severity of Covid‐19. METHODS: A retrospective and single‐centre study enrolled 98 laboratory‐confirmed Covid‐19 patients. Clinical data, electrocardiogram and CT features were collected and analysed using Statistical Package for the Social Sciences software. RESULTS: There were 46 males and 52 females, with a median age of 44 years, categorised into three groups, including mild, moderate and severe/critical Covid‐19. The rate of abnormal electrocardiograms in severe/critical group (79%) was significantly higher than that in the mild group (17%) (P = .027), which (r = 0.392, P = .005) positively related to the severity of Covid‐19 (OR: 5.71, 95% CI: 0.45‐3.04, P = .008). Age older than 60 years old, comorbidities, whether had symptoms on admission, fatigue, CT features, laboratory test results such as platelet count, lymphocyte cell count, eosinophil cell count, CD3+ cell count, CD4+ cell count, CD8+ cell count, the ratio of albumin/globulin decreased and D‐dimer, C‐reactive protein (CRP), B‐type natriuretic peptide (BNP), cardiac troponin I (cTnI) elevated were the risk factors for the increased severity of Covid‐19. The logistic model, adjusted by age, lobular involvement score and lymphocyte cell count, could be applied for assessing the severity of Covid‐19 (AUC, 0.903; Sensitivity, 90.9%; Specificity, 78.1%). CONCLUSIONS: Age >60 years old, chronic comorbidities, lymphocytopoenia and lobular involvement score were associated with the Covid‐19 severity. The inflammation induced by Covid‐19 caused myocardial injury with elevated BNP and cTnI level and abnormal electrocardiograms.

In December 2019, patients of Coronavirus Disease 2019 were identified. Up to 17 April 2020, it has been documented 84 149 laboratory-confirmed patients in China, and 1 994 456 patients in other countries. The World Health Organization (WHO) has announced Covid-19 is a public health emergency and adjusted the global risk level from "high" to "very high" on 28 February 2020.

With the number of confirmed patients rising around the world, on March 11st, WHO characterised Covid-19 as a pandemics. With the implementation of control measures, such as isolation and quarantine, the number of Covid-19 patients tended to stabilise. In this study, we aimed to analyse the clinical characteristics and computed tomography (CT) features of patients who confirmed Covid-19 in our hospital, and firstly explored the cardiac injury and electrocardiogram characteristics induced by Covid-19, therefore found the indicators and prediction models for the severity of Covid-19.

This research was a retrospective and single-centre study. All the patients with laboratory-confirmed Covid-19 admitted to the Fifth Affiliated Hospital of Sun Yat-sen University from 17 January to 16

February were enrolled. The Fifth Affiliated Hospital of Sun Yat-sen University is the only hospital assigned for the Zhuhai government responsible for the admission and treatment of Covid-19 patients.

The final date of follow-up was 3 March, and all the patients had clinical outcomes of discharge or death.

The medical records of all the patients were collected. And then we recorded the demographics, history of exposure, underlying diseases, clinical manifestations, laboratory parameters, electrocardiograms, chest CT, treatments, complications, outcomes and length of hospitalisation. The laboratory parameters included blood routine, blood chemical analysis, T lymphocyte count, liver and renal function assessment, markers of myocardial injury and cardiac function. The pulmonary lobe involvement was analysed by quantitative CT analysis, and each lobe was assigned a score ( Figure 1 ): score 0, 0% involvement; score 1, <25% involvement; score 2, 26%-49% involvement; score 3, 50%-75% involvement; and score 4, greater than 75% involvement.

There was a score of 0-4 for each lobe, with a total possible score of 0-20. 1 The diagnosis was according to the WHO interim guidance, and the diagnosis and treatment criteria of Covid-19 (trial version 6) advised by the general office of the national health commission of China. The Covid-19 diagnosis was confirmed by real-time polymerase chain reaction. The degree of severity of Covid-19 was defined as following: (1) Mild: slight clinical symptoms without CT abnormality. ① Body temperature returns to normal for more than three days; ② Respiratory symptoms improved significantly; ③ Pulmonary imaging showed that acute exudative lesions were significantly absorbed and improved; ④ Negative nucleic acid test for two consecutive respiratory specimens (sampling time: at least one day apart).

All data were analysed using Statistical Package for the Social Sciences (SPSS) version 26.0 software (SPSS Inc). Categorical variables were

• It is known that Covid-19 is a worldwide infectious disease, which causes complex clinical symptoms, even including induction and aggravation of cardiovascular disease, and death.

• The characteristics of individual symptom, risk factors, cumulative range of pulmonary infection and blood test indexes are the important factors affecting the prognosis.

• Earlier evaluation and treatment for reversible risk factors can improve the prognosis.

• Covid-19 confirmed patients were mainly imported, cluster, or infected by close contact, with low mortality and higher discharged rate. Progression of Covid-19 was strongly associated with the prognosis.

• The risk factors of age >60 years old, chronic comorbidities, lymphocytopoenia and lobular involvement score were malignantly associated with the Covid-19 severity, which was not parallel to the degree of fever.

• The inflammation induced by Covid-19 caused the myocardial injury with elevated BNP and cTnI level and abnormal electrocardiograms, which was firstly reported. described as frequency rates and percentages, and quantitative variables were described using mean (SD) 

In our study, all of 98 Covid-19 confirmed patients were investigated. There were 12 mild, 64 moderate, 19 severe, and three critically severe patients with a median age of 44 (33-62) years, of whom 46 (47%) patients were male, and 52 (53%) patients were female (P = .381). For the convenience of statistics, severe and critical patients were categorised as severe/critical. There was an obvious difference in age among the three groups (P < .001), as shown in ) patients. On the other hand, in the 61-80 year-old group, the incidence of severe/ critical patients (59%) was apparently higher than moderate (20%) and mild (0%) patients (P < .001). And there were no severe/critical patients observed in the 0-to 20-year-old group (P = .047). Notably, 77% of patients were clustering occurrences. The median of the incubation period was five days. Five patients had an incubation period exceeding 14 days, the longest of which was 27 days. 90 (92%) and 91 (93%) of patients did not have a history of smoking and alcohol, respectively. Thirty (31%) patients have comorbidities of hypertension (19%), diabetes (7%), pulmonary disease (7%), heart disease (6%), chronic kidney disease (2%), thyroid disorder (8%) and malignancy (4%). There were significant differences in whether had commodities on admission between severe/critical patients (55%) and moderate patients (27%) (P = .010).

We noticed that only 82 (83%) patients displayed symptoms on admission. And there was a remarkable difference in whether had symptoms between severe/critical (96%) and mild (58%) patients (P = .022). The most common symptom was fever (58%), with 42% of low fever (37.3℃-38℃), 15% of moderate fever (38.1℃-39℃), and 1% of high fever (39.1℃-41℃). Forty-two per cent of mid, 55% of moderate, and 77% of severe/critical patients of Covid-19 exhibited fever. Some severe/critical patients did not have a fever (Table 1) . Besides, patients who displayed fatigue in severe/critical group (32%) were much more than in the moderate group (8%) (P = .009).

The details were shown in Table 2 . The platelet count, lymphocyte cell count, eosinophil cell count, basophil cell count of the severe/ critical group were significantly lower than that of the moderate and mild groups, respectively. Fifty per cent and 68% of severe/critical patients had lymphocyte count, and eosinophil count decreased. In terms of T lymphocyte count, mature T lymphocyte (CD3+), inducible T lymphocyte (CD4+) and suppressor T lymphocyte (CD8+) cell counts were apparently reduced in the severe/critical group.

Forty-two per cent of patients in the mild group showed elevated alanine aminotransferase (ALT). The values of albumin and ratio of albumin/globulin in the liver function test were clearly decreased in the severe/critical group. Besides, 32% and 77% of severe/critical patients showed significantly increased D-dimer and C-reactive protein (CRP). For the markers of cardiac function and myocardial injury during hospitalisation (Table 3) , B-type natriuretic peptide (BNP) was remarkably increased in the severe/critical group (1076 pg/mL) compared with the moderate (77 pg/mL) and the mild (66 pg/mL) group (P < .001). Percentages of patients with elevated cardiac troponin I (cTnI) in the severe/critical group (27%) were distinctly higher than those in the moderate group (2%) (P = .002). F I G U R E 1 Transverse thin-section CT scan for the moderate patients of Covid-19. A, a 36-year-old male was admitted to the hospital because of cough for four days and fever for half-day and diagnosed as moderate of Covid-19. CT demonstrated pure ground-glass opacity in the left superior lobe. The lobular involvement score was one point, with the lobe involved less than 25%. B, a 36-year-old female was admitted to the hospital because of fever for 3 days, and diagnosed as moderate of Covid-19. CT revealed a subpleural confounding opacity lesion in the lower lobe of the left lung, and a patchy ground-glass opacity lesion with blurred boundaries in the lower lobe of the right lung (yellow arrows). The lobular score was one each in the left inferior lobe and the right inferior lobe, respectively, because of the involved area less than 25%. C, An 80-year-old female was admitted to the hospital because of diarrhoea, dyspnoea, anorexia, fatigue and muscular soreness, no fever or cough and diagnosed as severe of Covid-19. CT on admission showed diffuse lesions, mainly ground-glass opacity accompanied by partial consolidation, crazy-paving pattern in bilateral lungs, which were chiefly distributed under the pleura. The total lobular involvement score was 11, with two in the left superior lobe, two in the left inferior lobe, two in the right superior lobe, two in the right medial lobe and three in the right inferior lobe. The patient was also with atherosclerosis of aorta and coronary artery and a small amount of effusion in bilateral pleura. D, a 36-year-old male was admitted to the hospital because of generalised fatigue, muscular soreness for four days, and fever for three days, and diagnosed as severe of Covid-19. CT on admission indicated diffused irregular mixed patchy and ground-glass opacity lesions in bilateral lungs. The total lobular involvement score was 14, with three in the left superior lobe, three in the left inferior lobe, three in the right superior lobe, two in the right medial lobe, and three in the right inferior lobe 

Never 91 (93) 11 (92) 60 (94) 20 (91) - Diabetes 7 (7) 0 (0) 3 (5) 4 (18) .095

Pulmonary disease 7 (7) 0 (0) 3 (5) 4 (18) .095

Heart disease 6 (6) 0 (0) 2 (3) 4 (18) .051

Chronic kidney disease 2 (2) 0 (0) 1 (2) 1 (5) .576

Thyroid disorder 8 (8) 0 (0) 6 (9) 2 (9) .740 Chest distress 7 (7) 0 (0) 6 (9) 1 (5) .600

Dyspnoea 5 (5) 0 (0) 3 (5) 2 (9) .632 (Continues)

There were 49 patients performed electrocardiograph examinations during hospitalisation ( Table 3 ). The rate of abnormal electrocardiographs in severe/critical group (79%) was significantly higher than that in the mild group (17%) (P = .027). 

Mild patients were diagnosed with no pneumonia finding in CT images. Therefore, we only compared the difference in CT findings between the moderate and severe/critical group on admission (Table 4 ). The lobular involvement score in the severe/critical group Dizziness 6 (6) 0 (0) 6 (9) 0 (0) .345

Headache 8 (8) 0 (0) 6 (9) 2 (9) .740

.542

Myalgia/arthralgia 14 (14) 1 (8) 7 (11) 6 (27) .163

Mental state Anxiety 17 (17) 2 (17) 12 (19) 3 (14) .921

Depression 7 (7) 0 (0) 6 (9) 1 (5) .600

Acute respiratory distress syndrome

.062

Abnormal liver function 4 (4) 1 (8) 2 (3) 1 (5) .570

.347

.164

.347

.062

.164

.347

Three series decreased 1 (1) 0 (0) 1 (2) 0 (0) 1.000

Treatment outcomes .357 0.00 (0.00-0.01) ab <.001

Procalcitonin, ng/ mL

T lymphocyte count involvement (87% vs 45%, P < .001), ground-glass opacity (87% vs 61%, P < .001), mixed ground-glass opacity and patchy shadows (91% vs 58%, P < .001), and hydrothorax (27% vs 2%, P = .001) in the severe/critical group was conspicuously higher than that in moderate group. There were no significant differences in the conditions of tuberculosis and emphysema between the two groups. No obvious enlargement of lymph nodes or pulmonary fibrosis was found. 

The therapeutic regimens were shown in Table 6 . The outcomes and complications of these patients were shown in Sinus tachycardia 1 (2) 0 (0) 0 (0) 1 (7) .408

Sinus bradycardia 2 (4) 0 (0) 0 (0) 2 (14) .162

Ventricular premature beat

.408

Left deviation 2 (4) 0 (0) 2 (7) 0 (0) 

ST-segment elevation 1 (2) 0 (0) 0 (0) 1 (7) .408

ST-segment depression 1 (2) 0 (0) 0 (0) 1 (7) .408

T wave changes 5 (10) 0 (0) 2 (7) 3 (21) .374

Note: a and b, there were statistical significances between groups (2%), hypoproteinaemia (2%), mild anaemia (3%), granulocytopoenia (1%), three series (red blood cells, white blood cells and platelets) decreased (1%). There were conspicuous differences in whether had complications (6% vs 46%, P < .001), acute respiratory distress syndrome (ARDS) (0% vs 36%, P < .001) and septic shock (0% vs 14%, P = .021) between the moderate and the severe/critical group. It was worth mentioning that ARDS, septic shock, pneumothorax/pleural effusion, viral myocarditis, viral esophagitis, hypoproteinaemia and granulocytopoenia occurred only in severe/critical patients, and the incidences of ARDS (0% vs 36%, P < .001) and septic shock (0% vs 14%, P = .021) was significantly higher than that of moderate patients. On the other hand, 17% and 7% of patients presented anxiety and depression during hospitalisation, respectively.

The main findings for this cohort were as follows: Covid-19 confirmed patients were mainly imported, cluster, or infected by close contact. Zhuhai, close to Macau, is a famous seaside-tourism city, of which the epidemiological characteristics were different from that in Beijing. 3 The median incubation period was five days, consistent with the previous reports. 4 There were 5% of patients with the incubation period exceeding 14 days, and the most prolonged period was 27 days, suggesting that a longer duration of medical observation or active monitoring of quarantining contractors may be needed. The previous research showed that Covid-19 was more likely to infect older adult males with chronic comorbidities. 5 More details were analysed in our study and showed that age and chronic comorbidities, Patchy shadows 11 (11) 0 (0) 6 (9) 5 (23) .212

Mixed ground glass opacity+ patchy shadows 57 (58) 0 (0) 37 (58) 20 (91) .005

Hydrothorax 7 (7) 0 (0) 1 (2) 6 (27) .001

Enlargement of lymph nodes 0 (0) 0 (0) 0 (0) 0 (0) -Tuberculosis 2 (2) 0 (0) 1 (2) 1 (5) 1.000 Emphysema 9 (9) 0 (0) 6 (9) 3 (14) .873

Pulmonary fibrosis 0 (0) 0 (0) 0 (0) 0 (0) -Note: Only the moderate and severe/critical groups were compared.

The correlation and univariate logistic analysis of risk factors and CT score for evaluating the severity of Covid-19 9 Remarkably, our centre has reported that viral load in the asymptomatic patient was similar to that in symptomatic patients. 2 Besides, the degree of fever before admission was not parallel to the severity. Therefore the severity of Covid-19 could not be assessed by whether or not the fever was present or degrees of fever. Piperacillin and tazobactam sodium 6 (6) 0 (0) 2 (3) 4 (18) .051

Cefoperazone and sulbactam sodium 11 (11) 0 (0) 2 (3) a 9 (41) a <.001

Ceftazidime and avibactam sodium 1 (1) 0 (0) 0 (0) 1 (5) .347 

Vancomycin 2 (2) 0 (0) 0 (0) 2 (9) .062

Fluconazole 4 (4) 0 (0) 1 (2) 3 (14) .070

Improve immunity 

Extracorporeal membrane oxygenation 1 (1) 0 (0) 0 (0) 1 (5) .347

High flow breathing humidification therapy instrument

Noninvasive ventilation 13 (13) 0 (0) a 1 (2) b 12 (55) ab <.001

Tracheal intubation 2 (2) 0 (0) 0 (0) 2 (9) .062

Mechanical ventilation 2 (2) 0 (0) 0 (0) 2 (9) .062

Tracheotomy 1 (1) 0 (0) 0 (0) 1 (5) .347

Note: a and b, there were statistical significances between groups. especially in severe patients, who were prone to cytokine storms because of activated T-helper-1 cell responses. 10 Thirdly, according to the previous reports, 11 Additionally, different from previous report, 19 our study showed that not only the inferior lobes but also superior and medial lobes of the lung would be involved in moderate patients of Covid-19. Most of the severe/critical patients in our study presented mixed ground glass and patchy shadow, involving in the bilateral lung, more than two lobes, and any lobes.

There were some limitations in our study. Firstly, the clinical prognosis, including complete pneumonia absorption and negative nucleic acid detection, requires long-term follow-up. Secondly, it was not excluded that the abnormal electrocardiograms had existed before infection of Covid-19 in some patients. Thirdly, it was needed to evaluate further the effect of the logistic model on the long-term prognosis of Covid-19. Fourthly, CT score might be underestimated because of multiple, diffuse patchy and absorption of lesions on admission.

Covid-19 confirmed patients were mainly imported, cluster, or infected by close contact, with low mortality and higher discharged rate. The risk factors of age >60 years old, chronic comorbidities, lymphocytopoenia, and lobular involvement score were malignantly associated with the Covid-19 severity, which was not parallel to the degree of fever. The inflammation induced by Covid-19 caused the myocardial injury with elevated BNP and cTnI level and abnormal electrocardiograms. Progression of Covid-19 was strongly associated with the prognosis. Therefore, early diagnosis, identification and management of these patients with indicators to develop severe or critically Covid-19 collectively play essential roles in the reduction of mortality.

None.

The authors of this study declare that they each have no conflict of interest. 

Informed consent was obtained from all individual participants included in the study.

The data used in this study is not publicly available, but it might be available from the corresponding author upon reasonable request and permission from relevant Chinese Authorities.

Yubi Lin https://orcid.org/0000-0002-7625-3579

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